As­traZeneca’s big MYS­TIC tri­al ends a com­plete fail­ure as Imfinzi/treme­li­mum­ab com­bo flops on over­all sur­vival

Last year, As­traZeneca preached pa­tience af­ter ini­tial da­ta showed its check­point in­hibitor Imfinzi com­bined with their in-house CT­LA-4 drug failed to meet the pri­ma­ry end­point of pro­gres­sion-free sur­vival in a piv­otal lung can­cer tri­al. On Fri­day, that faith proved in vain as the im­munother­a­py al­so failed to im­prove over­all sur­vival in the keen­ly watched MYS­TIC tri­al.

The tri­al test­ed Imfinzi both as a monother­a­py and in com­bi­na­tion with an­oth­er check­point in­hibitor, treme­li­mum­ab, against chemother­a­py in treat­ment-naive pa­tients with stage IV non-small cell lung can­cer (NSCLC), a cru­cial are­na in the bat­tle for check­point drug dom­i­nance.

The phar­ma gi­ant $AZN con­ced­ed Fri­day morn­ing that the com­bi­na­tion — once con­sid­ered a cor­ner­stone of As­traZeneca’s check­point de­vel­op­ment strat­e­gy — ac­tu­al­ly per­formed worse than Imfinzi alone for the over­all sur­vival end­point, with a haz­ard ra­tio of 0.76 for the so­lo drug com­pared to an ane­mic 0.85 for the two to­geth­er.

Sean Bo­hen

While As­traZeneca’s pipeline has of­ten come up short, there have been a string of ma­jor suc­cess­es in on­col­o­gy for the com­pa­ny. This tri­al was con­sid­ered crit­i­cal in putting the brakes on the blitz­ing gains Mer­ck $MRK and Bris­tol-My­ers Squibb have made af­ter es­tab­lish­ing their lead in the lu­cra­tive front­line can­cer field. The study was al­so tout­ed by CEO Pas­cal So­ri­ot as an in­di­ca­tor of the British drug­mak­er’s val­ue as an in­de­pen­dent en­ti­ty, when it spurned Pfiz­er’s $PFE $118 bil­lion takeover bid in 2014

In a state­ment on Fri­day, As­traZeneca al­so sug­gest­ed that al­though sta­tis­ti­cal sig­nif­i­cance for over­all sur­vival had not been met, the da­ta mer­it­ed fur­ther analy­sis in ex­plorato­ry sub­groups. That’s not like­ly go­ing to in­spire much en­thu­si­asm.

Brad Lon­car

In MYS­TIC, “CT­LA-4 tru­ly of­fered no ben­e­fit or sig­nal at all”, said Brad Lon­car, man­ag­er of the Lon­car Can­cer Im­munother­a­py ETF. “I would think hard about these re­sults if I was one of the com­pa­nies out there de­vel­op­ing me-too or me-bet­ter CT­LA-4s (of which there are many). Giv­en its tox­i­c­i­ty pro­file and now the emerg­ing com­bo ef­fi­ca­cy we are see­ing in some of these can­cers out­side of melanoma, its win­dow is look­ing quite nar­row.”

As­traZeneca’s shares were al­so un­der pres­sure again on the fail­ure. Its stock is down more than 3% in pre-mar­ket trad­ing. Shares fell sharply last year on the PFS miss, evap­o­rat­ing some $14 bil­lion off the com­pa­ny’s val­ue.

Since that ini­tial set­back on MYS­TIC, though, As­traZeneca scored a big win with its PA­CIF­IC tri­al for Imfinzi, win­ning a sig­nif­i­cant mar­ket niche for it­self in stage III NSCLC. But the fail­ure here will sting, nev­er­the­less.

Chief med­ical of­fi­cer Sean Bo­hen spot­light­ed the suc­cess on the monother­a­py side, but con­ced­ed the key fail­ure:

We are en­cour­aged to see that Imfinzi monother­a­py ac­tiv­i­ty is in-line with that of the an­ti-PD-1 class in pre­vi­ous­ly-un­treat­ed pa­tients with Stage IV non-small cell lung can­cer; how­ev­er, we are dis­ap­point­ed that these re­sults missed sta­tis­ti­cal sig­nif­i­cance. We re­main con­fi­dent in Imfinzi as the cor­ner­stone of our IO pro­gramme and con­tin­ue to eval­u­ate its po­ten­tial in on­go­ing non-small cell lung can­cer tri­als, in­clud­ing Imfinzi and Imfinzi plus treme­li­mum­ab in com­bi­na­tion with chemother­a­py.


Im­age: Pas­cal So­ri­ot. AP IM­AGES

George Yancopoulos (Regeneron)

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Elias Zerhouni (Photo by Vincent Isore/IP3/Getty Images)

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Rather than interpret them, I thought it would be best to provide snippets straight from the interview.

On the Trump administration response:

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Researchers selected 45 healthy volunteers 18-55 years of age for the study. They were randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1, “a lipid nanoparticle-formulated, nucleoside-modified, mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein RBD.” Their responses were compared against the effect of a natural, presumably protective defense offered by a regular infection.

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The incidents are derailing plans to file for a near-term approval, which had been expected right about now.

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Joseph Kim, Inovio CEO (Andrew Harnik, AP Images)

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Tuesday morning Inovio, which has been struggling to get its Covid-19 vaccine lined up for mass manufacturing, put out a release that touched on virtually every hot button in pandemic PR.

There was, first and foremost, an interim snapshot of efficacy from their Phase I program for INO-4800.

Jan van de Winkel, Genmab CEO

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Randy Schatzman, Bolt CEO (Bolt Biotherapeutics)

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Bolt Biotherapeutics announced a $93.5 million Series C round led by Sofinnova Investments and joined by more than 9 others, including Pfizer Ventures and RA Capital Management. That money will go toward pushing the San Francisco biotech’s platform of innate immune-boosting warheads through its first trial on metastatic solid tumors and into several more.

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Akero had already said in March that its lead drug had beaten placebo in its Phase II trial, reducing liver fat by 14% in the highest dose group compared to 0.3% in placebo, according to MRI scans. But although NASH is an obesity-related condition and results from fatty buildup in the liver, the real immediate question for any therapy is whether it can resolve the fibrosis and inflammation that results from that buildup. Those data require biopsying the patients, a longer and more invasive process that was further complicated by a pandemic.